Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O6methylguanine-DNA methyltransferase

Zi Qiang Zhou, Diwi Manguino, Kristen Kewitt, Gabriel W. Intano, C. Alex McMahan, Damon C. Herbert, Martha Hanes, Robert Reddick, Yuji Ikeno, Christi A. Walter

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

O6-methylguanine (O6mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O6mG through a direct reversal mechanism by a protein termed O6-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O6mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB/FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB/FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacl transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacl. Tumors that arose in C3HeB/FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicate that spontaneous O6mG lesions induced hepatocellular carcinogenesis in C3HeB/FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis.

Original languageEnglish (US)
Pages (from-to)12566-12571
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number22
DOIs
StatePublished - Oct 23 2001

ASJC Scopus subject areas

  • General

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